Lycopene prevention of oxysterol-induced proinflammatory cytokine cascade in human macrophages: inhibition of NF-κB nuclear binding and increase in PPARγ expression

It is now well accepted that oxysterols play important roles in the formation of atherosclerotic plaque, involving cytotoxic, pro-oxidant and proinflammatory processes. It has been recently suggested that tomato lycopene may act as a preventive agent in atherosclerosis, although the exact mechanism of such a protection is not clarified. The main aim of this study was to investigate whether lycopene is able to counteract oxysterol-induced proinflammatory cytokines cascade in human macrophages, limiting the formation of atherosclerotic plaque. Therefore, THP-1 macrophages were exposed to two different oxysterols, such as 7-keto-cholesterol (4-16 mu M) and 25-hydroxycholesterol (2-4 mu M), alone and in combination with lycopene (0.5-2 mu M). Both oxysterols enhanced proinflammatory cytokine [interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor a) secretion and mRNA levels in a dose-dependent manner, although at different extent. These effects were associated with an increased reactive oxygen species (ROS) production through an enhanced expression of NAD(P)H oxidase. Moreover, a net increment of phosphorylation of extracellular regulated kinase 1/2, p-38 and Jun N-terminal kinase and of nuclear factor kappa B (NF-kappa B) nuclear binding was observed. Lycopene prevented oxysterol-induced increase in pro-inflammatory cytokine secretion and expression. Such an effect was accompanied by an inhibition of oxysterol-induced ROS production, mitogen-activated protein kinase phosphorylation and NF-kappa B activation. The inhibition of oxysterol-induced cytokine stimulation was also mimicked by the specific NF-kappa B inhibitor pyrrolidine dithiocarbamate. Moreover, the carotenoid increased peroxisome proliferator-activated receptor gamma levels in THP-1 macrophages. Taken all together, these data bring new information on the anti-atherogenic properties of lycopene, and on its mechanisms of action in atherosclerosis prevention. (C) 2011 Elsevier Inc. All rights reserved.